Thei Laura, Imm Jennifer, Kaisis Eleni, Dallas Mark L, Kerrigan Talitha L
Reading School of Pharmacy, University of Reading, Reading, United Kingdom.
University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
Front Neurosci. 2018 Sep 28;12:676. doi: 10.3389/fnins.2018.00676. eCollection 2018.
Alzheimer's disease is the most common form of dementia, it is estimated to affect over 40 million people worldwide. Classically, the disease has been characterized by the neuropathological hallmarks of aggregated extracellular amyloid-β and intracellular paired helical filaments of hyperphosphorylated tau. A wealth of evidence indicates a pivotal role for the innate immune system, such as microglia, and inflammation in the pathology of Alzheimer's disease. The over production and aggregation of Alzheimer's associated proteins results in chronic inflammation and disrupts microglial clearance of these depositions. Despite being non-excitable, microglia express a diverse array of ion channels which shape their physiological functions. In support of this, there is a growing body of evidence pointing to the involvement of microglial ion channels contributing to neurodegenerative diseases such as Alzheimer's disease. In this review, we discuss the evidence for an array of microglia ion channels and their importance in modulating microglial homeostasis and how this process could be disrupted in Alzheimer's disease. One promising avenue for assessing the role that microglia play in the initiation and progression of Alzheimer's disease is through using induced pluripotent stem cell derived microglia. Here, we examine what is already understood in terms of the molecular underpinnings of inflammation in Alzheimer's disease, and the utility that inducible pluripotent stem cell derived microglia may have to advance this knowledge. We outline the variability that occurs between the use of animal and human models with regards to the importance of microglial ion channels in generating a relevant functional model of brain inflammation. Overcoming these hurdles will be pivotal in order to develop new drug targets and progress our understanding of the pathological mechanisms involved in Alzheimer's disease.
阿尔茨海默病是最常见的痴呆形式，据估计全球有超过4000万人受其影响。传统上，该疾病的特征是细胞外淀粉样β蛋白聚集和细胞内高度磷酸化tau蛋白的双螺旋丝等神经病理学标志。大量证据表明，小胶质细胞等固有免疫系统和炎症在阿尔茨海默病的病理过程中起关键作用。阿尔茨海默病相关蛋白的过度产生和聚集会导致慢性炎症，并破坏小胶质细胞对这些沉积物的清除。尽管小胶质细胞不具有兴奋性，但它们表达多种离子通道，这些离子通道塑造了它们的生理功能。支持这一观点的是，越来越多的证据表明小胶质细胞离子通道参与了诸如阿尔茨海默病等神经退行性疾病。在这篇综述中，我们讨论了一系列小胶质细胞离子通道的证据及其在调节小胶质细胞内稳态中的重要性，以及这一过程在阿尔茨海默病中可能如何被破坏。评估小胶质细胞在阿尔茨海默病的发生和发展中所起作用的一个有前景的途径是通过使用诱导多能干细胞衍生的小胶质细胞。在这里，我们研究了在阿尔茨海默病炎症的分子基础方面已经了解到的情况，以及诱导多能干细胞衍生的小胶质细胞在推进这一知识方面可能具有的效用。我们概述了在使用动物模型和人类模型方面，关于小胶质细胞离子通道在生成相关的脑炎症功能模型中的重要性所存在的差异。克服这些障碍对于开发新的药物靶点和增进我们对阿尔茨海默病所涉及的病理机制的理解至关重要。
